Sharapova and Meldonium.

Remy

Administrator
So I found this article today that seems to explain a lot...remember Meldonium is a structural analogue of gamma-butyrobetaine, so presumably it would act the same way.

Specifically, "These results suggest that gamma-butyrobetaine can be taken up into organs, including the liver, of JVS mice, and transformed to L-carnitine. Consequently, administration of gamma-butyrobetaine may be more useful than that of L-carnitine itself for treatment of primary deficiency of carnitine due to a functional defect of the carnitine transporter."

Even better news is that it seems like it doesn't have an effect one way or another on the controls which is probably why it has a low toxicity profile.

J Pharm Pharmacol. 2001 Apr;53(4):527-33.
Effect of gamma-butyrobetaine on fatty liver in juvenile visceral steatosis mice.

Higashi Y1, Yokogawa K, Takeuchi N, Tamai I, Nomura M, Hashimoto N, Hayakawa JI, Miyamoto KI, Tsuji A.
Abstract
We pharmacokinetically examined the effect of gamma-butyrobetaine, a precursor of L-carnitine, on the change of fatty acid metabolism in juvenile visceral steatosis (JVS) mice, which have systemic L-carnitine deficiency due to lack of L-carnitine transporter activity.

The concentrations of total free fatty acid (FFA), palmitic acid and stearic acid in the liver of JVS mice were significantly higher than those in wild-type mice.

After intravenous administration of gamma-butyrobetaine (50 mg kg(-1)), the concentration of L-carnitine in the plasma of JVS mice reached about twice that of the control level and levels in the brain, liver and kidney were also significantly increased, whereas those in wild-type mice hardly changed.

Although the plasma concentrations of FFA in both types of mice were unchanged after administration of gamma-butyrobetaine, the concentrations of palmitic acid and stearic acid were significantly decreased. In particular, the liver concentration of FFA in JVS mice was decreased to the wild-type control level, accompanied by significant decreases in long-chain fatty acids, palmitic acid and stearic acid, whereas those in wild-type mice were not changed.

These results suggest that gamma-butyrobetaine can be taken up into organs, including the liver, of JVS mice, and transformed to L-carnitine. Consequently, administration of gamma-butyrobetaine may be more useful than that of L-carnitine itself for treatment of primary deficiency of carnitine due to a functional defect of the carnitine transporter.
 

Snow Leopard

Active Member
remember Meldonium is a structural analogue of gamma-butyrobetaine, so presumably it would act the same way.
Not at all, in fact Meldonium is an inhibitor of Gamma-butyrobetaine dioxygenase, so...

It would be interesting to see what effect it may have on humans... But keep in mind that enzymes like this have to be regularly injected intravenously - and the mice in the aforementioned study only had one dose before being sacrificed.
 

Remy

Administrator
Not at all, in fact Meldonium is an inhibitor of Gamma-butyrobetaine dioxygenase, so...
According to the package insert, this article and this article, meldonium is a structural analogue of gamma-butyrobetaine...

Pharmacodynamics. Mildronate® GX is a structural analogue of gammabutyrobetaine, a substance contained in every cell of human organism. Under the conditions of excessive stress meldonium restores balance between oxygen supply and its demand in cells, and removes toxic metabolic products accumulated in cells protecting them from damage; it also possesses tonic effect. In the result of its application the organism receives the possibility to withstand stress and quickly restore its energy reserves. Thanks to these properties Mildronate® GX is used for treatment of various cardiovascular system disorders and brain circulation impairment, as well as for improvement of physical and intellectual working efficiency. Decrease in carnitine concentration results in intensification of synthesis of γ-butyrobetaine which possesses vasodilating properties. In case of acute ischemic damage of myocardium, meldonium decelerates formation of necrotic zone, and reduces the duration of rehabilitation period.
But this article, interestingly enough, proposes that it creates an electron transfer system outside of the nervous system.


ABSTRACT
THE IDEA ABOUT EXISTENCE OF an electron transfer system outside the nervous system arises from simple consideration that if the signal transfer from nerve fibres to organs is of electric nature, a recurrent flow of electrons from effector cells to nervous system should exist in order to form a closed electric circuit. Several lines of scientific considerations all indicate that the gamma-butyrobetaine and gamma-butyrobetaine esters could perform this function. The gamma-butyrobetaine esterase activity, a necessary prerequisite for the existence of such a system, was detected in rat blood. Our recent results suggest that action of the anti-ischemic drug mildronate could be mediated, in part, by the stimulation of the gamma-butyrobetaine and gamma-butyrobetaine ester pathway and the production of the nitric oxide as a secondary messenger.
This same article speaks directly to the contradiction and meldonium's mechanism of action, though, with an alternate hypothesis.

Mildronate administration favours wound and ulcer healing [17-20],however carnitine biosynthesis and transport block should rather inhibit the cell proliferation [11].Mildronate interferes with membrane receptor and secondary messenger activity[21], in few hours it triggersDNA replication, repair and methylation [8,22,23].It is capable to trigger the RNA-polymerase activity in isolated neuronsin vitro[24].Increaseof the pre-mRNA synthesis was observed in ratliver, spleen, heart and intestine during 6 hours after the drug administration [25]. Decrease of the ADP-ribosylation of loosely-bound chromatinnon-histone proteins can be also observed soonafter the drug administration [26]. None of theabove effects could be explained by inhibition of the carnitine biosynthesis.
It is also suggested that meldonium is a cholinomimetic that increases eNOS. We've had lots of discussion lately on the role of choline in MECFS. Things that increase choline do seem to be helpful in a subgroup of us, whereas others have much more trouble tolerating them. It's worth noting that meldonium does seem to be a pretty potent vasodilator though.

It's clear as mud, but it seems obvious that meldonium is increasing, rather than inhibiting, carnitine synthesis, despite whatever action it might also have on GBB esterase.

Do we really think that more than 60 elite athletes would take something that inhibited performance? Whether they thought it was working, or it actually was doing something (even just covering up other agents), the effects were great enough for WADA to ban it and for Maria Sharapova to risk millions of dollars and her legacy on taking it. Those facts speak very loudly to me.

Unfortunately, the only rapid method of investigation is to bite the lemon, as Alex used to say. It seems the effects should be quite rapid one way or another. Maybe I am a good guinea pig since I seem to have over range carnitine anyway...
 

Remy

Administrator
Similar structural analogs usually don't work in exactly the same way in the body - those differences in structure can make a big difference, this is common amongst structurally similar drugs.
Yes, I agree. Structural analogues can sometimes (often?) have different functional effects.

But they've pretty well demonstrated in these papers that meldonium can increase carnitine synthesis due to negative feedback. I don't see why I shouldn't give them the benefit of the doubt that they are correct. Especially when the toxicity is so low. The 2013 Chinese study had not one serious adverse effect reported at doses of up to 1500 mg/day. The half life is only a few hours (though some are reporting terminal elimination is months which seems odd).

I understand, it's not for you. It may not be for me either but there is really only one way to find out!
 

Strike me lucky

Well-Known Member
Drugs in sport isnt just random stuff taken by athletes , its usually backed by alot of underground sports scientists . Interesting to know what else they currently use that so few know about and if there would be of benefit for sick people???
 

Snow Leopard

Active Member
Drugs in sport isnt just random stuff taken by athletes , its usually backed by alot of underground sports scientists.
I'm not convinced. These sports scientists are subject to the same biases as medical practitioners - fact is we don't really know if such drugs are effective until tested in blinded trials. Athletes may well be taking multiple supplements or drugs that are ineffective. That said, these scientists may have some interesting hypotheses worth testing in clinical trials.

Yes, I agree. Structural analogues can sometimes (often?) have different functional effects.

But they've pretty well demonstrated in these papers that meldonium can increase carnitine synthesis due to negative feedback. I don't see why I shouldn't give them the benefit of the doubt that they are correct.
Yes, the cell is going to try and compensate for any inhibition by ramping up other pathways - but this doesn't mean the final result is higher carnitine pathway activity - that is a bold claim that needs direct evidence.
 

Remy

Administrator
I'm not convinced. These sports scientists are subject to the same biases as medical practitioners - fact is we don't really know if such drugs are effective until tested in blinded trials. Athletes may well be taking multiple supplements or drugs that are ineffective. That said, these scientists may have some interesting hypotheses worth testing in clinical trials.



Yes, the cell is going to try and compensate for any inhibition by ramping up other pathways - but this doesn't mean the final result is higher carnitine pathway activity - that is a bold claim that needs direct evidence.
However my trial works out, I'm grateful for your input and skepticism because it has made me dig a lot deeper than I might have otherwise.
 

Remy

Administrator
Drugs in sport isnt just random stuff taken by athletes , its usually backed by alot of underground sports scientists . Interesting to know what else they currently use that so few know about and if there would be of benefit for sick people???
Right? Give me a day with Novak Djokovic's team because I do not for one second believe he is number one thanks to a gluten free diet alone.
 

Strike me lucky

Well-Known Member
Right? Give me a day with Novak Djokovic's team because I do not for one second believe he is number one thanks to a gluten free diet alone.
Any athlete i think would be interesting.

I find it interesting how sports teams and individuals all have their own drs. People other than drs can strap ankles. When alot of money is involved there will be science teying to improve performance, many start of legal and if shown to improve performance they ban them.

Spending some time with a few top horse trainers and i think one might also find some interesting things going on.

Alot of the time these substances are band because they work not because they are dangerous. But many times the big boses turn a blind eye especially to the top athletes. Better performances increases spectators and sponsorship. Also quicker recovery etc also keeps players on the field more so more money can be made from them. Also drug testing can help them get rid of someone thats not toeing the line, stop turning a blind eye and test an athlete positive who isnt doing what he's told and thats how they can get rid of them. Alot of positive tests are unknown athletes and its done as a token to make it appear their testing is keeping sport clean.

Imagine combining a drug protocol of an allround type athlete with abx avs and some ampligen. We might see a few 110% recoveries???
 

Remy

Administrator
From Metabolic Alchemy blog:

Mildronate has been a godsend to me. It has dramatically increased my workout performance, and it also has a mood-boosting and cognitive-enhancing aspect to it.

It doesn’t stimulate me per se, but it definitely relieves the malaise and “blah” feeling I would have every mid-afternoon of a stressful day.

My thinking is clearer, my energy is up, and my fatigue is down in a way that is leaving me hoping I could have a never-ending supply of this stuff.

And what’s more, its anti-ischemic effects are keeping my heart and cardio-vascular system in check. It helps blood flow and circulation in a way that is unique. It isn’t a vasodilator like L-Arginine or Sildenafil (a pde inhibitor I use regularly for blood pressure, vascularization, and well… you know…

Instead it just seems to make everything flow better in my body without any perceivable peripheral effects.

The creator of the drug, professor Ivars Kalvins, claims that Meldonium has never been found to have any kind of direct anabolic effects.

Instead, it acts as a cardioprotector that can protect cardiovascular system of athletes from ischemia under high physical workloads. He also says that most athletes actually should use it to diminish the negative effects associated with high-intensity trainings.I couldn’t agree more. High intensity training can be very beneficial to health.

But if you’re an athlete that is overtraining to any significant degree, then you are also probably pushing the limits of your adrenal and cardiovascular system.

With Mildronate, you get an insurance of sorts, something that helps promote a feeling of wellbeing that is also actually measurable.
More on how it works scientifically here:

http://www.metabolicalchemy.com/mildronate-russian-anti-ischemic-outperforms-expectations/
 

Remy

Administrator
FWIW, I found a US site that sells this for much less than the Russian site I used...and they even offer a 5 pill trial pack for $9.99. I love the idea of a trial pack! PM me if you want the details.
 

Remy

Administrator
@Strike me lucky, I tried the mildronate the other day finally. I'm not sure about it yet. I had kind of a panic attack and some mild anxiety after I took it. But, I also went out and mowed the lawn in 100 degree weather and was feeling pretty overwhelmed in general from the heat. That's not really a fair trial so I will try it again and stay inside. I might also try 250 mg vs 500 mg. I'll keep you posted!
 

Strike me lucky

Well-Known Member
Here's more on how meldonium/midronate works biochemically if anyone is still interested.

I find it VERY interesting that companies are starting to seriously look into drugs of this type for a number of conditions.
Above me other than works through carnitine metabolism.

Is it like comparing an ssri for serotonin with meldonium for carnitine??
 

Remy

Administrator
Above me other than works through carnitine metabolism.

Is it like comparing an ssri for serotonin with meldonium for carnitine??
I could be totally wrong but I thought of it more like LDN. Like blocking the receptor for a little bit which then leads to a more robust endogenous response.
 

Remy

Administrator
This article describes the mechanism as clearly as any I've seen...http://pubs.acs.org/doi/abs/10.1021/jm401603e

L-Carnitine is an important molecule for the regulation of cellular energy metabolism of fatty acids and glucose.

L-Carnitine is involved in long-chain fatty acid transport across the inner membrane of mitochondria, and it facilitates the transport of chain-shortened acyl groups produced in peroxisomes to mitochondria for further energy production.1

L-Carnitine also takes part in the regulation of glucose metabolism via modulation of free coenzyme A/acetyl-coenzyme A ratio.2

It is possible to shift the source of metabolic energy production from fatty acid β-oxidation to glucose oxidation by mildly reducing the amount of bioavailable L-carnitine;3,4 the survival of cardiac muscle cells under ischemic (low-oxygen) conditions is improved because aerobic glucose oxidation consumes less oxygen than fatty acid oxidation.5

γ-Butyrobetaine dioxygenase (BBOX), also known as γ-butyrobetaine hydroxylase (GBBH), EC 1.14.11.1, is an enzyme that catalyzes the formation of L-carnitine from 4-(trimethylammonio)butanoate, which is commonly known as γ-butyrobetaine (GBB).

Presently, 3-(1,1,1-trimethylhydrazin-1- ium-2-yl)propanoate (mildronate, meldonium, THP), which is structurally similar to the endogenous BBOX substrate, GBB (with an NH group replacing the CH2 of GBB at the C-4 position), is the only inhibitor of BBOX utilized pharmacolog- ically.

Mildronate induces cardioprotective effects by reducing the concentration of L-carnitine.6,7 Although mildronate is successful in the clinic,8 high dosages (1 g/day) are required, at least partly due to comparably inefficient inhibition of BBOX (Ki = 16 μM9).

A recent study has linked the amount of plasma L-carnitine with levels of its metabolite, trimethylamine N-oxide, and the increased risk of cardiovascular and diabetic complications.10,11 To investigate new L-carnitine-lowering agents, a mildronate-like drug with improved properties must be developed.
 

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